COMPANY OVERVIEW DINESH V. PATEL, PHD | PRESIDENT & CEO - FEBRUARY 2022

Page created by Jimmie Medina
 
CONTINUE READING
COMPANY OVERVIEW DINESH V. PATEL, PHD | PRESIDENT & CEO - FEBRUARY 2022
COMPANY OVERVIEW
Dinesh V. Patel, PhD | President & CEO

February 2022

                                         1
COMPANY OVERVIEW DINESH V. PATEL, PHD | PRESIDENT & CEO - FEBRUARY 2022
Forward-looking Statements
This presentation and the accompanying oral presentation contain forward-looking statements made pursuant to the safe harbor provisions of the
Private Securities Litigation Reform Act of 1995. All statements other than statements of historical facts contained in this presentation, including
statements regarding our future results of operations and financial position, business strategy, product candidates, capital resources, potential markets
for our product candidates, enrollment in our clinical trials, any potential impact on our business related to COVID-19, our potential receipt of milestone
payments and royalties under our Collaboration Agreement with Janssen Biotech, Inc., are forward-looking statements. In some cases, you can identify
forward-looking statements by terminology such as “anticipate,” “believe,” “continue,” “could,” “estimate,” “expect,” “intend,” “may,” “plan,” “potentially”
“predict,” “should,” “will” or the negative of these terms or other similar expressions.
The forward-looking statements made in this presentation involve known and unknown risks, uncertainties and other important factors that may cause
our actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by
the forward-looking statements. These forward-looking statements are subject to risks and uncertainties, including those discussed in Protagonist’s
filings with the Securities and Exchange Commission, including in the “Risk Factors” and “Management’s Discussion and Analysis of Financial Condition
and Results of Operations” sections of most recently filed periodic reports on Form 10-K and Form 10-Q and subsequent filings and in the documents
incorporated by reference therein. Because forward-looking statements are inherently subject to risks and uncertainties, some of which cannot be
predicted or quantified and some of which are beyond our control, you should not rely on these forward-looking statements as predictions of future
events. The events and circumstances reflected in our forward-looking statements may not be achieved or occur and actual results could differ materially
from those projected in the forward-looking statements. Except as required by applicable law, we do not plan to publicly update or revise any forward-
looking statements contained herein, whether as a result of any new information, future events, changed circumstances or otherwise.
This presentation concerns products that are under clinical investigation and which have not yet been approved for marketing by the U.S. Food and Drug
Administration. They are currently limited by Federal law to investigational use, and no representation is made as to their safety or effectiveness for the
purposes for which they are being investigated. The trademarks included herein are the property of the owners thereof and are used for reference
purposes only. Such use should not be construed as an endorsement of such products. Nothing contained in this presentation is, or should be
construed as, a recommendation, promise or representation by the presenter or Protagonist or any director, employee, agent or advisor of Protagonist.
This presentation does not purport to be all inclusive or to contain all the information you may desire.

                                                                                                                                                               2
COMPANY OVERVIEW DINESH V. PATEL, PHD | PRESIDENT & CEO - FEBRUARY 2022
Protagonist Therapeutics
Peptide-based Medicines

        Discovering novel peptide therapeutics through a proprietary technology platform and
        developing them to address unmet medical needs in both rare and common diseases

      POTENCY

 1     Computational                                     3
       Vectrix, Clusters
                            2
                                                              Peptide Chemistry      CLINICAL ASSETS
                                                                 SAR, Leads
                                  Phage Libraries
                                       Hits
                                                                                        Rusfertide
     Vectrix ®   Clusters

                                                                                         PN-943

     STABILITY                                                                           PN-235
4                                                        6
                                                             Systemic Availability
       Oral Stability       5                                     Formulation
      Peptidomimetics               GI-Restricted               SAR, Transport
        GI Assays               Targeted GI absorption
                                      & delivery

                                                                                                       3
COMPANY OVERVIEW DINESH V. PATEL, PHD | PRESIDENT & CEO - FEBRUARY 2022
Product Portfolio
Addressing Unmet Needs in Multiple Indications with Multi-billion Dollar Market Potential

   PROGRAMS          CANDIDATE      STUDY                   PHASE 1                          PHASE 2                Key Milestones
HEMATOLOGY & BLOOD DISORDERS

                                   VERIFY                                                              PV Ph3
                                               Polycythemia Vera (PV) Ph3 initiation
                                   300-11                                                               • Initiation in Q1 2022

                                   REVIVE      PV Ph2 PoC                                               • Resuming enrollment
                     rusfertide    300-04                                                               • Data updates at EHA & ASH 2021
    Hepcidin
                     (PTG-300)
    Mimetic
                        s.c.       PACIFIC     PV Ph2 in Patients with Elevated Hematocrit              • Dosing resumed into OLE
                                    300-08                                                              • Data presented at ASH 2021

                                                                                                        • Clinical PoC established
                                   300-06      Hereditary Hemochromatosis (HH) Ph2 PoC
                                                                                                        • Data presented at ASH 2021
INFLAMMATORY & IMMUNOMODULATORY DISEASES

Oral GI Restricted                                                                                      • 150 patient study
  a4b7-Integrin       PN-943        IDEAL      Ulcerative Colitis (UC) Ph2 PoC                          • Enrollment complete
   Antagonist                                                                                           • Topline data Q2 2022

                                                                                                       Plaque Psoriasis Ph2
      Oral                                                                                              • 240 patient study initiated Q1 2022
    IL-23R            PN-235      FRONTIER 1   Plaque Psoriasis Ph2b PoC initiation
   Antagonist                                                                                          IBD Ph2
                                                                                                         • Initiation in 2H 2022

                                                                                                                                                4
COMPANY OVERVIEW DINESH V. PATEL, PHD | PRESIDENT & CEO - FEBRUARY 2022
Rusfertide (PTG-300): Hepcidin Mimetic
To Potentially Address Unmet Needs in Both Rare & Common Diseases

                                                                    5
COMPANY OVERVIEW DINESH V. PATEL, PHD | PRESIDENT & CEO - FEBRUARY 2022
Polycythemia Vera
Disease Background

 Myeloproliferative neoplasm characterized by
 excessive production of red blood cells (RBCs)
                                                                 Treatment goal
   • Characterized by Janus Kinase 2 (JAK2) mutation        is to control hematocrit
                                                                   level
COMPANY OVERVIEW DINESH V. PATEL, PHD | PRESIDENT & CEO - FEBRUARY 2022
Rusfertide for Polycythemia Vera
Overview of Current Status and Recent Progress

Continued Progress Underway
 • Orphan, Fast Track and Breakthrough designations
  • Clinical update presented at ASH 2021
  • Updated IB and ICF, enhanced safety surveillance measures and inclusion/exclusion criteria following brief (21-day)
    clinical hold. Enrollment and dosing have resumed.
  • Clinical studies
    − Phase 2 REVIVE randomized withdrawal study has resumed enrollment; data updates provided at EHA and ASH 2021
    − Phase 2 PACIFIC PV study with elevated hematocrit (48% or higher) has resumed dosing into open-label extension;
      data presented at ASH 2021
    − Regulatory interactions continue to finalize and enable Phase 3 PERSIST study initiation in Q1 2022; Phase 3 design
      presented at ASH 2021

Rusfertide (PTG-300)
 • Potential for managing hematocrit per NCCN guidelines without creating iron deficiency, while improving symptoms
  • Close consultation underway with regulators
  • Natural hormone mimetic therapy for PV

                                                                                                                            7
COMPANY OVERVIEW DINESH V. PATEL, PHD | PRESIDENT & CEO - FEBRUARY 2022
Polycythemia Vera
Current Treatment Options

                                                                               Hydroxyurea                                            Besremi*
               Phlebotomy                                                     +/- Phlebotomy                                         (ropeginterferon   Jakafi
                                                                                                                                        alfa-2b-njft
                                                                                                                                        injection)

• Treatment goal is to maintain HCT ≤ 45%                   • Recommended when HCT cannot be                                 • Approved for HU resistant/intolerant
• HCT control may be erratic with up and                      controlled, or in high-risk patients                             patients
  down excursions from 45%                                  • Potential long-term side effects                               • ~5,300 patients/yr treated**
• Can lead to iron deficiency                               • Some patients reluctant to use                                 • ~25% develop intolerance or resistance
                                                              chemotherapeutic agents                                        • Potential side effects include cytopenia

                                                           CHRONIC TREATMENT OVER ~20 YEARS

                         *Newly FDA approved, undergoing U.S. commercial launch; uncertain place in the therapeutic paradigm at present
                                 **Represents patients treated with Jakafi; uncertain of Besremi population due to recent approval
                        1. MPN Landmark Survey 2017, Trinity Primary Research 2019                                                                                        8
COMPANY OVERVIEW DINESH V. PATEL, PHD | PRESIDENT & CEO - FEBRUARY 2022
Understanding PV Patient Journey
Evaluating the Unmet Need of PV Patients in US

                                                                                                                              Real world PV patient treatment data
                                                                                                                                          (2018-2019)1
  • Evaluation of 28,306 PV patients treated in
    2018-2019
  • Hematocrit levels: lab tests of 4,264 patients                                                                                                 Treated PV Patients
                                                                                                                                                           N = 28,306

           Key Findings in three categories

                                                                                                                                                             >2 HCT
                                                                                                                                                            Lab Tests
   Treatment           Hematocrit                                 Thrombotic risks                                                                           N= 4,264
    patterns          management to                                 and events
                     NCCN guidelines

                                                                                                                                               Representative of treated
                                                                                                                                                    PV population

                      1   Symphony Patient Journey Data Large, representative, and longitudinal source of healthcare claims data that captures over 290MM patients with over 78% of all prescription claims and 60% of all
                          medical claims. Medical, hospital, and prescription history is captured across treatment settings and payers with history back to 2003                                                             9
COMPANY OVERVIEW DINESH V. PATEL, PHD | PRESIDENT & CEO - FEBRUARY 2022
Real World PV Patient Treatment Data
Evaluation of 28,306 PV Patients Treated in 2018-19

                    • Predominant treatment is phlebotomy, regardless of risk
                    • Hydroxyurea is the most commonly used cytoreductive agent
    Treatment       • Combination of hydroxyurea and phlebotomy commonly used to control HCT
     patterns

                    • Hematocrit not managed to NCCN guidelines, Only 22% patients had all HCT tests
Rusfertide: Mechanistic Rationale for Potential Treatment of PV

                       Polycythemia Vera                                                          MOA of rusfertide
     FERROPORTIN
     transports iron                                                                                 RUSFERTIDE
                                                              Elevated                                                             Normalized
                                                             Hematocrit                                                            Hematocrit
                           Splenic                                          FERROPORTIN
                           macrophage                                                                             RBC PRODUCTION
  HEPCIDIN                              EXCESSIVE RBC PRODUCTION
   Inhibits
 ferroportin                                                                                                                       45%
                                                            45%

                                                                          SERUM IRON

  serum
    iron

      Transferrin
     delivers iron                                                                IRON DELIVERY

                                                                                                                                                11
Phase 2 Study of Rusfertide in PV Patients (REVIVE)
GOAL: Maintain Hematocrit
Effect of Rusfertide on Phlebotomy Frequency in REVIVE Study

Phlebotomy only (N=31, 49%)                                                                 Phlebotomy + cytoreductive (N=32, 51%)
     Pre-Treatment    Treatment                          Open Label Extension (OLE)                     Pre-Treatment    Treatment                           Open Label Extension (OLE)
     -28 to 0 weeks   28 weeks                                   52 weeks                               -28 to 0 weeks   28 weeks                                    52 weeks

                                                                                                                                         Randomization
                                  Randomization

                                                                  p< 0.001                                                                                             p< 0.001

                                                  Screening        Part 1 – Dose Finding    Part 2– Blinded Withdrawal      Part 3 – Open Label Extension

                                                                           Phlebotomy      Last dose on study

                                                                                                                                                  Data as of September 30, 2021           13
Baseline Characteristics of Study Participants in REVIVE Study

Characteristics (n = 63)
AGE                                                                   THERAPIES

  Range              27-76 years (Mean = 56.3 yrs)                         PHL only                     31 (49.2%)
GENDER                                                                     PHL + HU                     18 (28.6%)
  Females            18 (28.8%)
                                                                           PHL + IFN                    8 (12.7%)
  Males              45 (71.4%)
                                                                           PHL + RUX                    3 (4.8%)
RISK
                                                                           PHL +Multiple Agents         3 (4.8%)
  Low                28 (44.4%)
                                                                      NUMBER OF PHL IN 28 WEEKS PRIOR
                     35 (55.6%)
  High
                     [Age based – 36.5%, Thrombotic events – 19.0%]        2-3                          15 (23.8%)

DURATION SINCE PV DIAGNOSIS                                                4-5                          33 (52.3%)
Rusfertide Controls HCT and Ferritin in REVIVE Study

                    Hematocrit                                                                                           Ferritin

                                     Screening        Part 1 – Dose Finding   Part 2/3 – Blinded Withdrawal/OLE   Part 3 – Open Label Extension

           Box whiskers extend up to 1.5 times interquartile range.
                     Data as of September 30, 2021                                                                                                15
Improvement in MPN-TSS Scores Following Rusfertide in REVIVE Study
                                                                                                                 Problems with Concentration

                                                                                                          2.0           1.9

                   Total Symptom Score                                                                    1.5

                                                                                            Paried Mean
   20                                                                                                     1.0                                   0.9

          16.3
                      15.2
                                          14.6                                                            0.5
   15

                                                      11.4
                                                                                                          0.0
   10                                                                                                               Baseline                  Week 28
                                                                                                                     N=24                      N=24

   5                                                                              Worst Level of Fatigue                                                    Itching-Pruritus
                                                                             4                                                                2.5         2.3
                                                                                   3.2
   0
                                                                             3                                    2.7                         2.0
        Baseline     Week 8             Week 16      Week 28
                                                                                                                                                                          1.6
         N=62         N=56               N=50         N=24

                                                               Paired Mean
                                                                                                                                              1.5

                                                                                                                                Paired Mean
                                                                             2
                                                                                                                                              1.0
                                                                             1
                                                                                                                                              0.5

                                                                             0                                                                0.0
                                                                                 Baseline                       Week 28                                 Baseline       Week 28
                                                                                  N=24                           N=24                                    N=24           N=24
                     Data as of September 30, 2021                                                                                                                               16
Adverse Events Experienced on Rusfertide in REVIVE Study

System Organ Class. - Preferred term                          AE n (%)
                                                                          • Most Drug related AEs were Grade 1 or 2
Total number of Subjects                                         63
                                                                          • No Grade 4 or 5 Events
No. of subjects with treatment-emergent AE                    55 (87)
Blood and Lymphatic Disorders                                 12 (19.0)
                                                                          • SAE’s: Syncope, peripheral artery aneurism,
                                                                            gastroenteritis, chest pain, AML, squamous cell
     Anemia                                                   9 (14.3)
                                                                            carcinoma (skin), melanoma & basal cell
Gastrointestinal disorders                                    20 (31.7)     carcinoma
   Nausea                                                     8 (12.7)
                                                                          • Injection site reaction (ISRs) were most common
Infections and infestations                                   11 (17.5)
                                                                            and associated with 28.1% of injections. All ISRs
Metabolism and nutrition disorders                            9 (14.3)      were transient, and no patient discontinued due
Musculoskeletal and connective tissue disorders               27 (42.9)     to ISR.
Nervous system disorders                                      21 (33.3)   • One subject stopped treatment due to AE within
Psychiatric disorders                                         7 (11.1)      2 weeks (asymptomatic thrombocytosis)
   Insomnia                                                    4 (6.3)
                                                                          • No clinically significant laboratory abnormalities.
Renal and urinary disorders                                    5 (7.9)
                                                                          • No Anti Drug Antibody response was noted in
Respiratory                                                   14 (22.2)
                                                                            any patient
Skin and subcutaneous tissue disorders                        23 (36.5)
      Pruritis                                                9 (14.3)

                              Data as of September 30, 2021                                                                       17
Conclusions from Phase 2 REVIVE Study

 Rusfertide therapy resulted in rapid, sustained and durable hematocrit control without
 clinically meaningful changes in white blood cell and platelet counts

 Rusfertide demonstrated similar efficacy in all categories of patients, independent of the PV
 patient risk category or concurrent therapy with hydroxyurea, interferon or ruxolitinib

 Subjects have been treated up to 1.5 years with subjects remaining
 essentially phlebotomy-free

 Benefits from rusfertide treatment were noted in patient reported outcomes as assessed
 by MPN-SAF Total Symptom Score

 Results to date suggest that rusfertide is well tolerated; the most common adverse
 events were grade 1 or 2

                                                                                                 18
PACIFIC: Open-Label Phase 2 PV Study in Subjects with high hematocrit (>48%)

 Patient met the WHO criteria for PV diagnosis and had a baseline hematocrit (HCT) >48%,
 and a history of ≥3 HCT values >48% in the prior year prior

 All adult males or females with both high-risk and low-risk criteria treated with
 phlebotomy alone or with concurrent cytoreductive therapy were enrolled

 Initial dose: (40 mg SQ twice weekly). After hematocrit was
PACIFIC Phase 2 Study (High Hematocrit)
Therapeutic Phlebotomies Prior to and on Rusfertide
                           Age/Sex                                                                            First Dose

                     005   52/F

                     004   47/M

                     006   69/F

                     007   62/M

                     011   41/M

                     008   70/M

                     009   60/M

                     001   49/F
          Subjects

                     003   63/M

                     015   53/F

                     018   55/M

                     016   58/M

                     014   57/M

                     002   46/M

                     019   53/M

                     013   63/M

                     012   41/M

                     020   56/M

                     017   72/F

                     010   66/M

                                     -52   -48   -44   -40   -36   -32   -28   -24   -20   -16   -12    -8   -4   0     4   8     12   16    20   24   28   32   36   40

                                                                                                       Weeks

                                                             Screening               PTG-300            Dose decision           Phlebotomy

                             Data as of September 30, 2021                                                                                                                 20
Rusfertide Controls HCT and Reduces RBC Count in PACIFIC Study

          Rusfertide Rapidly Controls HCT                                               Rusfertide Rapidly Reduces RBC Count

                                                                                  8

                                                                                  7

                                                                  RBC (10^6/uL)
                                                                                  6
HCT (%)

                                                                                  5

                                                                                  4

                                                                                  3
                                                                                  N     20       18        17      13       11       9       4        3
                                                                                      Baseline   Wk 4     Wk 8    Wk 12   Wk 16     Wk 20   Wk 24   Wk 28

                                  Weeks                                                                             Weeks

               Screening              PTG-300              Mean                                       Screening           PTG-300             Mean

                           Data as of September 30, 2021                                                                                                    21
Adverse Events in Ongoing PACIFIC Study
System Organ Class                                                       All AEs
Preferred term                                                            n (%)
Total number of Subjects                                                    20
No. of subjects with treatment-emergent AE                               16 (80.0)

Blood and Lymphatic System                                                3 ( 15.0)
                                                                                      • Most Drug related AEs were Grade 1 or 2
    Thrombocytosis                                                        3 ( 15.0)

General disorders and Administration Site Conditions                     10 (50.0)    • One subject stopped treatment due to AE
    Injection Site Erythema                                               9 (45.0)      (Thrombocytosis without bleeding or
    Injection Site Induration                                             5 (25.0)      thrombosis; Grade 4 according to
    Injection Site Pruritus                                               2 (10.0)      investigator)
    Injection Site Swelling                                               5 (25.0)
                                                                                      • Injection site reaction (ISRs) were most
    Pyrexia                                                               2 (10.0)
                                                                                        common and associated with 68% of
Nervous system disorders                                                  5 (25.0)
                                                                                        injections. All ISRs were transient, and no
    Headache                                                              2 (10.0)
                                                                                        patient discontinued due to ISR.
Skin and subcutaneous tissue disorders                                    5 (25.0)

    Erythema                                                              4 (20.0)    • No anti-drug antibody response was noted in
    Pruritus                                                              4 (20.0)      any patient
Vascular disorders                                                        2 (10.0)

    Hypertension                                                          2 (10.0)

                                         Data as of September 30, 2021                                                                22
Conclusions from PACIFIC High Hematocrit Study

 Rusfertide induction therapy with twice weekly dosing is effective at rapidly achieving target hematocrit
 below 45% without phlebotomy in all PV patients.

 Rapid hematocrit control:
Rusfertide Phase 3 PV Study Design (VERIFY Study)
Enrollment Criteria, Primary Endpoint, Key Secondary Endpoints, Additional Assessments

 Enrollment Criteria:                                            Primary Endpoint:
 • Adult patients with PV per 2016 WHO Criteria                  • Absence of phlebotomy eligibility based on
 • High risk and low risk patients                                 hematocrit control between weeks 20-32
 • Patients requiring frequent phlebotomy
 • With or without cytoreductive therapy
 • Exclusion of patients with invasive cancer in prior 5 years
                                                                 Additional Assessments:
                                                                 • Durability of response weeks 32-52
 Key Secondary Endpoints:
                                                                 • Open-label treatment to evaluate long-term
 • Number of phlebotomies                                          effects and safety
 • Symptom improvement scores
 • Safety

The Phase 3 study design capitalizes on the successful outcome of the 60-plus patient open-label Phase 2 REVIVE Study

                                                                                                                        24
Randomized, Double-blind, Placebo-Controlled Phase 3 PV Study (VERIFY)
    VERIFY Study of N~250 subjects

                                 Part 1a                                 Part 1b                               Part 2
Screening               Double Blind (Weeks 0-32)                                                                                       Safety
 (Up to 4                                                      Durability of Response                Long Term Safety Follow-up       Follow-up
 W eeks)             Dose Titration   Primary Efficacy             (Weeks 32-52)                           (Weeks 52-156)             (4 W eeks)
                     (Weeks 0-20)      (Weeks 20-32)

                                                                                   NDA + MAA filings

                   Rusfertide + Ongoing Therapy
                              (n=125)
 Screening                                                        Rusfertide
                                                                       +                             PV Therapy + Rusfertide
                    Placebo + Ongoing Therapy                   Ongoing Therapy
                             (n=125)

                                                         Week 32                      Week 52                                     Week 156
        Week 0                                       Primary Endpoint                Durability of                                  End of
       Randomize                                    Analysis (Unblind)                Response                                    Treatment
         (1:1)

   The Phase 3 study design capitalizes on the successful outcome of the 60-plus patient open-label Phase 2 REVIVE Study

                                                                                                                                              25
PV Commercial Opportunity & Rusfertide Positioning

                    LOW BURDEN                                              MODERATE BURDEN                                                   HIGH BURDEN       MF/AML
                   (
Rusfertide Market Preparation: PV Indication
Intend to Demonstrate Clinical & Economic Value Before Approval

    Value      Distribution      Market             HEOR               Prescriber          Competitive             Positioning
 Proposition    Channels         Access                                Education           Landscape                Strategy

Patients       Patient access   Pricing &       Health Economics &   Raise awareness of   Existing and future   Leader in the
                                Reimbursement   Outcomes Research    PV, unmet need and   treatments            treatment of PV
Prescribers
                                Strategy        for assessing        NCCN Guidelines
Payers
                                                economic burden
                                                and benefit of
                                                treatment

                                                                                                                                  27
Hereditary Hemochromatosis (HH)
Disease Prevalence and Treatment

              HH is predominately due to genetic mutation, leading to a deficiency of hepcidin in the body
                        Rusfertide, if approved, could serve as a hormone replacement therapy

                                                                                                                              Excessive iron
                                                                                  Phlebotomy is the
          Iron                            Unmet medical                                                                      accumulation in
                                                                                   only therapeutic
        overload                          need in specific                                                                      heart, liver,
                                                                                      option; no
        disease                           subpopulations                                                                     pancreas, skin,
                                                                                   approved drugs
                                                                                                                               joint tissues

                                                   If untreated, iron overload can cause
        hepatomegaly, diabetes mellitus, skin hyperpigmentation, cardiomyopathy, diastolic dysfunction, heart failure, cirrhosis, etc.

                         Source: Porter JL, Rawla P. Hemochromatosis. (Updated 2020 Jun 18], https://www.ncbi.nlm.nih.gov/books/NBK430862/      28
Proof of Concept Phase 2 Study in Hereditary Hemochromatosis

   SCREENING          MONTH 1         MONTH 2           MONTH 3           MONTH 4           MONTH 5         MONTH 6

Pre-study
Phlebotomy
and Liver MRI
                                   Adverse event monitoring, dose adjustment, PK and PD (iron parameters)

   •   Six-month, open-label study in 16 HH patients in maintenance phase of iron depletion
   •   Stable pre-study phlebotomy for ≥6 months; requiring ≥3 phlebotomies/12 months or ≥4
       phlebotomies/15 months
   •   Patients with end-organ damage or on chelation therapy or erythrocytapheresis were excluded
   •   Self-administered SC doses once or twice weekly
        •   Dose adjusted to maintain serum iron & TSAT
Hereditary Hemochromatosis
    Summary of Results in HH and Next Steps
•       Significantly reduction in number                                                 •   Maintained liver iron                                        •   Lowered serum iron and TSAT
        of phlebotomies                                                                       content
                                                                                                           N=14
                                        N=16
                           0.6
PN-943 and IL-23 Receptor Antagonists
Oral Targeted Investigational Therapies for IBD and non-IBD indications
                                                                          31
IBD: Paradigm Shift Toward Targeted Oral and Combination Therapy
A growing multi-billion dollar market

                2019: ~ $14B sales1                                                                           2029: projected ~ $24B sales 1

         Historical IBD Treatment Paradigm                                                                  Emerging IBD Treatment Paradigm

                                                                                                 Injectable mAbs with safer MOAs
                                                                                                • α4β7 integrin: Entyvio® (~ $4B sales 2020)
                                                                                                • IL-12/IL-23: e.g., Stelara®

       TNF mAbs dominated IBD Therapy                                                                                                           Potential
                                                                                                 Oral Targeted Therapy for IBD                  Future of
      • Injectable TNF mAbs – Blockbusters
                                                                                                Protagonist: mAb Validated Pathways                IBD
         – Humira® & Remicade®
                                                                                                                                               Oral Combo
      • Significant room for improvement                                                        • PN-9432 (α4β7 integrin)
                                                                                                                                                 Therapy
         – Low response rates / loss of response                                                • IL-23Rs

         – Safety concerns - black box warnings
                                                                                                Other Oral Approaches: New Targets
                                                                                                • S1P1: e.g., Zeposia®
                                                                                                • JAK*: e.g., Xeljanz®, Rinvoq®
                                                                                                    *black box warnings

                        1
                            GlobalData: Global Drug Forecast and Market Analysis to 2029; 7 Major Markets: US, EU5, JP
                        2   Investigational product candidate, not approved                                                                                 32
Oral, Gut-Restricted, a4b7-Integrin Peptide Antagonists: PN-943
Fully Owned and Validated Asset and Approach

 Clinically Validated, IBD Specific Target
 • T cell homing regulated by α4β7 integrin and MAdCAM-1 interaction
 • MAdCAM-1 expressed only in GI vasculature
 • Entyvio (Vedolizumab) approved for Crohn’s & UC
  – ~$5B fiscal 2021 sales
 • Superior efficacy for Entyvio vs. Humira in 52 wk Ph3B VARSITY study

                                                                                                                                  Briskin M, et al Am J Pathol. 1997;151:97-110

   PN-943: Validated, Gut-restricted Approach
   • First-in-class potential as an oral, GI-restricted α4β7-specific antagonist
   • PN-943 is ~3x more potent in numerous pre-clinical studies & Ph1 NHV study
     vs 1st generation candidate PTG-100 (DDW, 2019)1
       – PTG-100 showed signals of clinical efficacy in Ph2a UC trial
         (Gastroenterology, 2021)2                                                                                                                                    Vs.
   • PN-943 global Ph2 150 patient study in UC patients in progress
   • Study completion anticipated 2Q 2022*

                  1Mattheakis,                                                                              2Sandborn,  W. J., Mattheakis, L. C., Modi, N. B., Pugatch, D., Bressler, B., Lee, S., ... & Gupta,
                               L., Tang, T., Venkataraman, S., Rao, N., Wang, L., Zhao, L., ... & Liu, D.
                  Y. (2019). The oral α4β7 integrin specific antagonist PN‐10943 is more effective than     S. (2021). PTG-100, an oral α4β7 antagonist peptide: preclinical development and phase 1 and
                                                                                                                                                                                                                  33
                  PTG‐100 in multiple preclinical studies. Gastroenterology, 156(Suppl 6), S80-S81.         2a studies in ulcerative colitis. Gastroenterology, 161(6), 1853-1864.
PN-943: First-in-Class Oral a4b7 Integrin Antagonist

PN-943 superior to first generation PTG-100
 • In vitro potency and binding kinetics with similar robust selectivity
 • Blood PD effects of local target engagement in 3 species with oral stability and limited blood exposure
  • Efficacy in rodent colitis model

PN-943 was advanced into clinical development in 2019
 • Oral GI-restricted approach validated by PTG-100 PROPEL Ph2a data

Future Potential Assessed in Surveys with Gastroenterologists
 • MEDACorp 2020: “oral anti-integrins were found to be the most exciting unapproved drug class in UC”
 • COWEN 2020: The most exciting agent (among 10) in development for moderate-severe IBD was Protagonist’s
   PN-943, tied with PTG-200

                                                                                                             34
PN-943 vs. PTG-100: Blood %RO based Clinical Proof-of-Concept
Ph1 NHV Single Ascending Dose Study

          PTG-100 Ph2 UC PoC                                                                                               PN-943 vs PTG-100 Ph1 Data
             Ph2A Study                      PTG-100                                                                  Ph1 SAD                                                         Ph1 MAD, Day 14
                UC                            900 mg
                                                 44%                                                                                                                                                           96%
        Histologic Remission                                                                                                              94%
                                                                                                      100                  83%                                             100
                                                (7/16)                                                                              74%                                                        80%
                                                                                                                                                                                                         74%
                                                 16%                                                  80                                                                   80

                                                                                        Maximum %RO
                                                                                                                                                  74%

                                                                                                                                                             Maximum %RO
         Clinical Remission*                                                                                                                                                                                            74%
                                                (3/19)
                                                                                                      60                                                                   60

                                                                                                      40                                                                   40

             Ph 1 Study                      PTG-100                                                  20                                                                   20
               NHVs                          1000 mg
                                                                                                       0                                                                    0
                                                                                                             100 mg    300 mg       1000 mg                                      100 mg   300 mg          1000 mg
             % Blood RO                         74%

       *based on blinded endoscopic re-reads                                                                                                 PTG-100          PN-943
       * Clinical remission: SFS ≤1, RBS = 0, ESS ≤1

                                                                                                PN-943 vs. PTG-100 Ph1 NHV study
      Established 74% blood RO in healthy
      subjects as a translational benchmark                                                     • Higher effect on blood %RO confirms ~3x superiority of PN-943 vs. PTG-100
                                                                                                            – PN-943 300mg blood %RO > PTG-100 1000 mg blood %RO effect
                                                                                                • Saturable target engagement at 1000 mg QD dose

                     Modi, N. B., Cheng, X., Mattheakis, L., Hwang, C. C., Nawabi, R., Liu, D., & Gupta, S. (2021). Single‐and Multiple‐Dose Pharmacokinetics and Pharmacodynamics of PN‐943, a Gastrointestinal‐Restricted Oral
                     Peptide Antagonist of α4β7, in Healthy Volunteers. Clinical pharmacology in drug development.                                                                                                                 35
PTG-100 Ph2A Efficacy Similar to Other IBD Targeted Therapy Drugs

                                                  Oral/JAK          Oral/S1P1          Injectable        Injectable            a4b7 integrin
                                             20
                                                                                       a4b7/aEb7          MAdCAM        Injectable           Oral
                                             18   17.6
                                                                                                                        16.9
                                                                                                                                      15.8
                                             16                     15.2               15.3       15.3
          % Patients in Clinical Remission

                                             14
                                                                                                         12.3
                                             12              11.6                                                              11.5
                                                                                                                                                11

                                             10                                                                   9.6                                Active
                                                                               9
                                                                                                                                                     Placebo
                                             8
                                                                                                                                                     Delta
                                                         6               6.2
                                             6                                                                             5.4
                                                                                                                                          4.8
                                             4
                                                                                                            2.7
                                             2
                                                                                              0
                                             0
                                             N= 905 234             132 65              81 43            284 73         225 149         19 21
                                                  Tofacitinib       Ozanimod          Etrolizumab        SHF-647*        Entyvio       PTG-100
                                                                                                                                      900 mg q.d.
                                                    *Anti-MadCam mAb
                                                    * No central read endoscopy (Entyvio)                                                                      36
IDEAL: PN-943 Phase 2 UC Study
      Adult Patients with UC
               N≈150                                  Part-1: Induction           Part-2: Extended Treatment Period
Eligibility:
                                                  Active Drug 450 mg BID (n=50)
• Moderate – Severe UC
• 3-Component Mayo Score 5-9 points
                                      Randomize
Inclusion:                             (n=150)    Active Drug 150 mg BID (n=50)             PN-943
• Bio-naïve and bio-experienced
  patients
                                                  Placebo BID (n=50)
Primary endpoint:
• Clinical Remission at Week 12
Secondary endpoints:                   5 weeks              12 weeks                         40 Weeks
                                                                                                              Week 52
• Endoscopic, histopath, mucosal
Exploratory endpoints:
• Blood %RO, FCP

                                           Enrollment is complete
                     Study completion and preliminary data readout anticipated in Q2 2022

                                                                                                                        37
The Outcome of Phase 2 IDEAL study will Inform Phase 3 decisions
  • Phase 2 data in UC with various candidates spanning different mechanism of actions
       – Large confidence intervals, influenced by study design, duration, size, demographics, & criteria
       – Phase 2 outcomes has generally predicted efficacy in Phase 3

                                    Translating HHistorical Ph2, Ph3, and Approval Data in UC 2 ➞ Phase 3 ➞ Approval*
                                                                                                               Clinical Remission Delta
                                Candidate                                       MoA                                                                                                    Approval
                                                                                                                Phase 2                         Phase 3
                  Vedolizumab (Entyvio®)1                                a4b7 integrin                             19%                            11.5%                                       ✓
                  Ozanimod (Zeposia®)2                                          S1P                                10%                            12.4%                                       ✓
                  Upadacitinib (Rinvoq®)3                                        JAK                              19.6%                         21/29.5%                     TBD (✓ RA; black box)
                 *Cross trial comparisons complicated by different inclusion criteria, patient populations, primary endpoint definitions, timing of primary endpoint, phase of clinical development

  • Phase 2 data will provide specific guidance for phase 3 program on
       – Dose selection
       – Powering of registrational primary and secondary endpoints
1. Feagan, B. G., Greenberg, G. R., Wild, G., Fedorak, R. N., Paré, P., McDonald, J. W., ... & Vandervoort, M. K. (2005). Treatment of ulcerative colitis with a humanized antibody to the α4β7 integrin. New England Journal of Medicine, 352(24), 2499-
   2507; Feagan, B. G., Rutgeerts, P., Sands, B. E., Hanauer, S., Colombel, J. F., Sandborn, W. J., ... & Parikh, A. (2013). Vedolizumab as induction and maintenance therapy for ulcerative colitis. New England Journal of Medicine, 369(8), 699-710.
2. Sandborn, W. J., Feagan, B. G., Wolf, D. C., D’Haens, G., Vermeire, S., Hanauer, S. B., ... & Olson, A. (2016). Ozanimod induction and maintenance treatment for ulcerative colitis. New England Journal of Medicine, 374(18), 1754-1762; Sandborn,
   W. J., Feagan, B. G., D’Haens, G., Wolf, D. C., Jovanovic, I., Hanauer, S. B., ... & Danese, S. (2021). Ozanimod as induction and maintenance therapy for ulcerative colitis. New England Journal of Medicine, 385(14), 1280-1291.
3. Danese, S., Vermeire, S., Zhou, W., Pangan, A., Siffledeen, J., Hébuterne, X., ... & Pannaccione, R. (2021). OP24 Efficacy and safety of upadacitinib induction therapy in patients with Moderately to Severely Active Ulcerative Colitis: Results from the
   phase 3 U-ACHIEVE study. Journal of Crohn's and Colitis, 15(Supplement_1), S022-S024.; Vermeire, S., Danese, S., Zhou, W., Pangan, A., Greenbloom, S., D’Haens, G., ... & Panaccione, R. (2021). OP23 Efficacy and safety of upadacitinib as
   induction therapy in patients with Moderately to Severely Active Ulcerative Colitis: Results from phase 3 U-ACCOMPLISH study. Journal of Crohn's & Colitis, 15(Suppl 1), S021.

                                                                                                                                                                                                                                                            38
Oral, IL-23 Receptor Specific Peptide Antagonist: PN-235
Janssen Partnership

                                                                                  p19 antibody:                               Stelara®: Blocks both
   Objective                                                                      Blocks IL-23 pathway                        IL-23 & IL-12 pathways

   • Extend the Stelara® franchise and transition from injectable to oral
                                                                                                          p19      p40                          p35         p40
     targeted therapy                                                             IL-23R Antagonist:
                                                                                  Blocks IL-23 receptor
         –   Stelara approved for psoriasis, psoriatic arthritis, Crohn’s, UC     & IL-23 pathway

                                                                                                                   IL-12Rβ1

                                                                                                                                                            IL-12Rβ1
                                                                                                                                                 IL-12Rβ2
                                                                                                          IL-23R
   Terms                                                                                                                      CELL MEMBRANE

   • May 2017: Partnership initiated
   • $87.5M in upfront and development milestones received to date
                                                                                                             IL-23                                   IL-12
   • Eligible for about additional $900M in milestones, up to double digit
     royalties, US co-detailing rights
      − Study initiation milestones: $25M (psoriasis) and $10M (IBD)

   Status                                                                                  Stelara® is a key Janssen franchise
   • Focus on the PN-235 candidate, with its superior potency and PK/PD                    • ~$7.7B total global sales in 2020
     profile, for IBD and non-IBD indications
       – PN-235 (JNJ-77242113): Ph1 completed in 2021; advancing in
         psoriasis indication in FRONTIER 1 study, initiated in early 2022, and                                    Vs.
         in IBD indications in 2H 2022

                                                                                                                                                                       39
Janssen FRONTIER 1 Phase 2b Plaque Psoriasis (PsO) Study
                             Screening                Treatment                  Safety Follow-up    Week 156
Adult Patients with PP                                                                                 End of
                          (Up to 4 Weeks)*           (Weeks 0-16)                      (4 Weeks)
        N≈240                                                                                        Treatment

 Eligibility:
                                                      Dose 1 QD
 • Moderate – Severe PP
                                                                                 PN-943
 Inclusion:
                                                      Dose 2 QD
 • BSA > 10%

                                         Randomize
 • PASI > 12
                                                      Dose 3 QD
 Primary endpoint:                                                                Safety Follow-up
 • PASI > 75 at Week 16                               Dose 1 BID

                                                      Dose 3 BID

                                                       Placebo

                                          Week 0                        Week 16
                                         Randomize                  Primary Endpoint

                               $25M milestone payment when third patient is dosed
                                                                                                            40
PROTAGONIST THERAPEUTICS
Protagonist Team and Financials

                                  41
                                       41
Protagonist Team
Experience & Expertise in Drug Discovery, Clinical Development, and Commercialization

                          Dinesh Patel, PhD            President & CEO

                          David Liu, PhD               CSO, Head of Discovery & Pre-Clinical Dev

                          Samuel Saks, MD              Clinical Development Advisor

                          Suneel Gupta, PhD            Chief Development Officer

                          Donald Kalkofen              Chief Financial Officer

                          Tracy Woody                  EVP, Commercial Strategy

                          Matthew Gosling, JD          EVP, General Counsel

                          Mohammad Masjedizadeh, PhD   EVP, Chief Technical Officer

                          Scott Plevy, MD              EVP & Therapeutic Head, Gastroenterology

                          Ashok Bhandari, PhD          SVP, Discovery Chem & Process Res

                          Paula O’Connor, MD           SVP, Clinical Development

                          Abha Bommireddi, MS          SVP, Program Management

                          Carter King, MBA             SVP, Business Development

                          Nishit Modi. PhD, MBA        SVP, Clinical Pharmacology

                          Sarita Khanna, PhD           SVP, Biometrics

                                                                                                   42
Financial Highlights
Financial resources forecast extends through full year 2024

             $352.5M                                                   2024                                            47.7M

              CASH & SECURITIES                                  CASH & SECURITIES                               SHARES OUTSTANDING
             As of September 30, 2021                          provide financial resources                        as of September 30, 2021
                                                            forecast through full year 2024*

              *This includes our initial CMC investments in preparation for a phase 3 with PN-943 in UC, should we achieve positive Phase 2
              results, we will be in a position to share more on any next steps after the data read out for PN-943 in Q2 2022                 43
Upcoming Catalysts in 2022 and Beyond
Significant opportunities to unlock and capture value in the 12-24 months ahead

                                                Anticipated Events of 2022
 Products                                                                                                                2023
                              Q1                             Q2                    Q3                  Q4

Rusfertide       •   VERIFY: Ph3 250 patient                                                                   •   Ph3 enrollment
             1       PV study initiation                                                                ASH        completion (1H)
                 •   REVIVE: Ph2 PV study                   EHA                                                •   Ph2 randomization
             2       (300-04) continuation                                                                         results (Q1)

             3 •     2nd indication: HH market opportunity and next steps

PN-943                                             •   IDEAL: Ph2 150                                          • Ph3 UC study
                                               4       patient UC study                                           initiation*
                                                       topline results                                         *assuming positive Ph2 data

PN-235           •   Ph2 initiation – Plaque                                                                   •   Ph2 plaque psoriasis
             5       psoriasis                                              6 •   Ph2 initiation in IBD (2H)       study results
                 •   $25M milestone                                           •   $10M milestone
             7
Discovery      •     Nomination of oral hepcidin mimetic candidate
             8
Pre-Clinical   •     Nomination of new development candidate – new target for new indication(s)
                                                                                                                                             44
THANK YOU

            45
You can also read